This project is designed to "map" thje three dimensional structure and electronic character of a series of dopamine transporter ligands. The mapping will include the overall geometry of the drug molecules as well as the electronic characteristics defined by net atomic charges, electron density distribution, electrostatic potentials, and intermolecular interaction energies. To calculate these quantities, carefully measured experimental x-ray diffraction data will be collected on a selected set of analogs with varying degrees of dopamine uptake inhibition and receptor affinity. The specific compounds chosen for charge density analysis are: (1) 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)-piperazine dihydrochloride GBR 12,909) is a compound selective for the dopamine transporter that inhibits cocaine binding at low concentrations, (2) benztropine mesylate is a potent dopamine uptake inhibitor that competitively inhibits GBR 12,909 binding, (3) mazindol is a dopamine uptake inhibitor that competitively inhibits GBR 12,909 binding, (4) methylphenidate is a well-known stimulant that binds potently and somewhat selectively to the dopamine transporter. Routine x-ray crystal structures of several derivatives of cocaine, mazindol, GBR, methylphenidate, and benztropine will be completed in order to determine the three-dimensional structures and conformations of these molecules. This information in conjunction with the electronic structure of the molecules chosen for charge density analysis will be used to model the cocaine receptor site(s). This will give us a cleared understanding of the charge distribution and structural requirements for drug binding and action that occur at this site.